3-lower alkyl enolethers of 3-keto-2-carboxy steroids and derivatives thereof



United States Patent The present invention relates to of steroidal2-carboxy-acids and having the following formula:

the 3-alkyl-enol-ethers to the derivatives thereof,

where R is a member selected from the group comprising hydrogen andmethyl; R is a member selected from the group comprising hydroxy,acyloxy and C H (this latter being a Z-methyl-isohepty group); R is amember selected from the group comprising hydrogen and a lower alkyl; Ris a straight or branched alkyl radical having up to 4 carbon atoms; R,is a member selected from the group comprising OH, OMe, OEt, CH Cl, NHCNS, CNO,

S O NH-( iNHR5, and NH-ii-NH-Rs R is a member of the group comprisinghydrogen, alkyl of from 1 to 6 carbon atoms, ribosyl, 2', 3', 5-tri-O-benzoyl-ribosyl, 2-deoxyribosyl and 3,5-di-O-benzoyl-2- deoxy-ribosyl, Xbeing a single or a double bond.

Such compounds have been found to be very useful for therapy of thecardiovascular diseases and hyperlipidemia and as affecting thehypophysary gonadotropic secretion.

Such compounds are also very important intermediates in the preparationof useful steroidal compounds.

The 3-keto-2-carboxy-esters are employed as starting materials and aredirectly obtained by the condensation of the 3-keto derivatives withdiethyl-carbonate in dimethylsulfoxide in the presence of sodium-amide;by pyrolyzing 2-glyoxylalkoxy-3-ketones (Nelson R. A. and Schutz R. N.,J. Am. Chem. Soc. 80, 6630 (1958)); (Djerassi C.; Hart P. A. and Beard,C., J. Am. Chem. Soc. 86, 85, 1964); or by alkaline saponification of2-cyano-3-enolethers (U.S. appln. 214,848, August 6, 1962) or3,3-ethylendioxy-steroids, these latter having been prepared throughdioxolanation of 2-cyano-3-keto-steroids (U.S. appln. 279,630, filed May10, 1963).

The invention will be better explained by the following examples whichare not intended as a limitation thereof.

EXAMPLE 1 2 u-carboxyethy lester-J 7 u-methyl-S a-aizdrostane-17fl-0l-3-0ne To a solution of 17oz-methy1-5a-andr0stane-1718-01-3- one(3 parts) in dimethylsulphoxide (30 parts), sodium amide (3 parts) wasadded with stirring at room temperature. Twenty parts of adiethyl-carbonate solution in dimethylsulphoxide (1:1) were added after20 minutes, the stirring continuing for two hours. The obtained solutionwas neutralized by adding a saturated monosodic-phosphate solution,thoroughly diluted and filtered. The

crude product, dissolved in dimethylene chloride, was purified bychromatography on silica gel, and from the methylene chloridezbenzene6:4 fraction,2u-carboxyethylester-17o--methyl-5a-androstane-17,8-ol-3-one (1.2 parts)was obtained, M.P. 166-168 C.

EXAMPLE 2 Zoe-carboxymethy lester-J 7 ix-methyI-S a-androstane-17,8-01-3-0ne At room temperature, sodium methoxide (1.8 parts) wasadded to a solution of 17u-methyl-5a-androstane- 17fl-ol-3-one (1.4parts) in dimethyl-sulphoxide (15 parts) with stirring. After 30minutes, 15 parts of a solution (1:1) of dimethylcarbonate indimethylsulphoxide was added over a period of two hours. The thusobtained solution was neutralized with a monosodic phosphate solution,diluted with water and filtered. The crude product, dissolved inchloroform, was chromatographed on silicagel and from the methylenechloridezbenzene 5:5 fraction, 20c carboxymethylesther-17a-methyl=5ix-androstrane- 17fl-ol-3-one (0.43 part) wasobtained.

EXAMPLE 3 Z-cyano-S-ethoxy-I 7a-methyl-h-androst-Z-ene-l -01 A 20%sodium hydroxide solution (7.4 parts) was added dropwise over a periodof 30 minutes into a slurry of (2,3 d) isoxazole 17a methyl 5aandrostane- 17fl-ol-3-one (5.28 parts) in ethanol parts) anddiethyl'sulphate (4.83 parts), the temperature being about 5 C. Stirringwas carried on for two hours. The solution obtained by filtration wasconcentrated to a small volume, diluted with water, extracted withether, repeatedly Washed with alkali and evaporated to dryness. Bycrystallization from methanol, 2 cyano 3ethoxy-17amethyl-5a-androst-2-ene-175-01 (3.8 parts) was obtained.

EXAMPLE 4 2-cyan0-3-eflzoxy-cholest-2-ene To a slurry of(2,3d)-isoxazole cholestane (3.64 parts) in ethanol (60 parts),diethyl-sulphate (2.42 parts) was added; then a 20% sodium hydroxidesolution (3.7 parts) was added, while the temperature was kept between 5and 10 C. Stirring was continued for two hours; the filtered solutionwas evaporated to a small volume, then diluted with water, and extractedwith ether. The organic phase was washed several times with alkali, thenevaporated to drryness to give, after crystallization from methanol,1.97 parts of 3-ethoxy-2-cyano-cholest-2-ene, M.P. 192-194 C. (a) =77(chloroform).

EXAMPLE 5 2-cyano-3-ethoxy-cholesta-2,4-diene Following the processdescribed in the above example, from 2 parts of(2,3-d)-isoxazole-cholesta-4-ene as starting material,2-cyano-3-ethoxy-cholest-a-2,4-diene (0.98 part) was obtained.

EXAMPLE 6 2-cyano-3-elhoxy-1 7a-methyl-androstwZA-diene-l713-01Following the process described in Example 4, from 4.6 parts of(2,3-d)-isoxazole-17a-metl1yl-androst-4-ene17,8- ol, 2 cyano 3ethoxy-17a-methyl-androsta-2,4-diene- 1713-01 (3.2 parts) was obtained.

EXAMPLE 7 2-cyan0-3-eth0xy-1 7a-methyl-estra-2,4-diene-1 713-0l To aslurry of Zea-cyano-17a-methyl-estr-4-ene-17/3-01-3- one (1 part) indioxane (9 parts), was added 1 part of triethyl anthofarmate, and then0.1 part of p-toluenesulphonic acid. The mixture was kept at roomtemperature for 24 hours, then one part of pyridine was added and thesolution was evaporated to a small volume. The mixture was diluted withether, repeatedly extracted with alkali, washed with water andevaporated to dryness. By crystallization from methanol-ethyl ether,2-cyano-3-ethoxy-17amethyl-estra-2,4-diene-175-01 (0.72 part) wasobtained.

EXAMPLE 8 2-cyan0-3-e thoxy-androsta-2,4-diene-1 7 [3-01 The process ofExample 7 was followed, except that 2u-cyano-androst-4-ene-3-one 17fi-ol(2 parts) was used as starting material.2-cy-ano-3-ethoxy-androsta-2,4-diene- 1713-01 (1.37 parts) was obtained,M.P. 120l23 C.

EXAMPLE 9 2-cyano-3-methoxy-ch0lesta-2,4-diene According to Example 4,from 1.8 parts of (2,3-d)- isoxazole cholestane, 2 cyano 3 methoxycholesta- 2,4-diene (1.02 parts) was obtained by treating with dimethylsulphate.

EXAMPLE 10 2-cyan0-3-butoxy-cholest-Z-ene A solution of2-cy-ano-ch0lestane-3-one (25 parts) in toluene (750 parts) was refluxedwith n-butanol (90 parts) and p-toluenesulphonic-acid (1.4 parts) for 15hours, an azeotropic mixture of water-toluene being distilled off. Thesolution was neutralized with pyridine parts), repeatedly washed withalkali, then washed with water, and evaporated to dryness.2-cyano-3-butoxycholest-2-ene (22 parts) was obtained; M.P. 140142 C.;(a) =+66 (chloroform).

EXAMPLE 11 2-cyan0-3-but0xy-ch0lesta-2,4-diene Following the procedureof Example 10, except that 2a-cyano-cholest-4-ene-3-one parts) are used,2- cyano-3 butoxy-cholesta-2,4-diene (11.2 parts) was obtained, M.P.120-122" C.

EXAMPLE 12 2-cyan0-3-butoxy-androsta-2,4-diene-1 7 fl-ol Following theprocedure of Example 10, except that 2acyano-androst-4-ene-17B-ol-3-one(12 parts) was used 10.8 parts of 2-cyano-3-butoxy-androsta-2,4-diene-173-0l were obtained, M.P. 102-104 C.

EXAMPLE 13 2-cyan0-3-butoxy-andr0sta-2,4-diene-1 7fi-acetoxy2-cyano-3-but-oxy-androsta2,4-diene-17/3-01 (2 parts) was dissolved inpyridine (6 parts), and acetic anhydride (3 parts) was added thereto.The solution was kept at room temperature over night, then diluted withwater and filtered; by crystallization from "methanol, 1.92 parts of 2cyano 3 butoxy androsta 2,4, diene 17B- acet-oxy were obtained, M.P.129132 C.

EXAMPLE 14 2-cyan0-3-butoxy-estra-2,4-diene-1 75-01 Following theprocedure of Example 10, except that 2acyano-estr-4-ene-17/3-01-3-one(6.8 parts) was used, 2- cyano-3-butoxy-estra-2,4-diene-176-01 (6.2parts) was obtained.

EXAMPLE 15 2-cyan0-3-butoxy-l 7a-methyl-andr0sta-2,4-diene-1 7B-0lFollowing the procedure of Example 3, except that nbutyl iodide wassubstituted for diethyl sulphate from (2,3-d)-isoxazole-androst-4-ene-17 8-01 parts), 2-cyano-3-butoxy-17a-methyl-androSta-2,4-diene-175-01 (12 parts) was obtained.

EXAMPLE 16 2-carb0xylic acid-3-n-but0xy-andr0sta-2,4-diene-I 7,8-0l

A solution of 12 parts of potassium hydroxide in 12 parts of water wasadded to a solution of 2-cyano-3-n- 4butoxy-androsta-2,4-diene--01-17-acetate (4 parts) in ethylene glycol(60) parts; the mixture was refluxed for 10 hours, with stirring, thencooled, diluted with water, filtered and acidified. After filtering andwashing with water, 2 carboxylic acid 3 n butoxy androsta-2,4-diene-17B-ol (2.2 parts) was obtained, M.P. 210-212 C., bycrystallization from ethyl acetate.

EXAMPLE 17 2-carb0xylic acid-3-n-butoxy-andr0sta-2,4-diene-1713-01Following the procedure of Example 16, from 2.4 parts of2-cyano-3-n-butoxy-androsta-2,4-diene-17 8-01 were obtained 1.8 parts of2-carboxylic acid-3-n-butoxy-androsta- 2,4-diene-17fl-ol; M.P. 211-212C.

EXAMPLE 18 Z-carboxylic acid-3-n-butoxy-androsta-Z,4-diene- 1 7,8-0l-17-acetate 2-carboxylic acid-3-n-butoxy-androsta-2,4-diene-1713-01 (1part) was dissolved in pyridine (4 parts) and 2 parts of aceticanhydride were added thereto. After 24 hours, the solution was dilutedwith water, acidified and filtered. After crystallization frommethanol-ether, 2-carboxylicacid-3-n-butoxy-andr0sta-2,4-diene-17fl-ol-17-acetate (1.02 parts) wasobtained.

EXAMPLE 19 2-carboxylic acid-3-n-but0xy-17a-methyl androsta-2,4-diene-17B-ol The process of Example 16, was followed, except that 2 cyano 3 nbutoxy 17a methyl androsta 2,4 diene-17,B-ol (2 parts) was used.2-carboxylic acid-3-nbutoxy-17a-methyl-androsta-2,4-diene-1713-01 (1.12parts) was obtained.

EXAMPLE 2O Z-carboxylic acid-3-n-but0xy-ch0lesta-2,4-diene Following theprocedure of Example 16, starting from2-cyano-3-n-butoxy-cholesta-2,4-diene (18 parts), 2-carboxylic acid-3-n-butoxy-cholesta-2,4-diene (12 parts) was obtained.

EXAMPLE 21 2-carb0xylic acid-3-n-but0xy-estra-2,4-diene-17fi-0l Aprocess similar to that of Example 16, except that 2-cyano-3-n-butoxy-estra-2,4-diene-17B-ol (12 parts) was used;2-carboxylic acid-3-n-butoxy-estra-2,4-diene-17fl-ol (9.3 parts) wasobtained.

EXAMPLE 22 Z-carboxylic acid-methylester-3-n-butoxy-androsta-2,4-diene-1 7 fl-ol To a slurry of Z-carboxylicacid-3-n-butoxy-androsta- 2,4-diene-17fi-ol (3.4 parts) in benzene (15parts) was added a 2.8% diazomethane solution in ethyl ether (20 parts).The mixture was kept at room temperature for 2 hours, then evaporated tohalf of its volume, washed with a 5% sodium bicarbonate solution, andthen with water to neutrality. By evaporating to dryness, 2-carboxylicacid methylester 3 n butoxy androsta 2,4- diene-17,B-ol (3.2 parts) wasobtained.

EXAMPLE 23 Z-carboxylic acid-methylester-3-n-but0xyandrosta-2,4-diene-17 fi-ol-l 7 -acetate Following the procedure of Example 22, from 6.2parts of 2 carboxylic acid 3 n butoxy androsta 2,4-diene-17fi-ol-17-acetate, 601 parts of 2-carboxylic acidmethylester 3 nbutoxy androsta 2,4 diene 17pol-17-acetate were obtained.

EXAMPLE 24 2-carb0xylic acid-methylester-3-n-butoxyestra-2,4-diene-17,8-01

2 vcar boxylic acid methylester 3 n butoxy estra- 2,4-diene-17fi-ol(3.75 parts) was obtained following the procedure of Example 22, from3.8 parts of Z-carboxylic acid-3-nabutoxy-estra-2,4-diene-1713-01.

EXAMPLE 25 Z-carboxylic acfd-methylester-3-n-but0xy-cholesta. 2,4-dieneThe procedure of Example 22 was followed, except that 2-carboxylicacid-3-n-butoxy-cholesta-2,4-diene (6 parts) was used as startingmaterial, and Z-carboxylic acid methylester 3 11 butoxy cholesta 2,4diene (6.05 parts) was obtained.

EXAMPLE 26 2-carb0xylic acid-m ethylester-3-n-but0xy-17a-methylandr0sta-2,4-diene-175-01 From 2-carboxylicacid-3-n-butoxy-17a-methyl-androsta-2,4-diene-l7fl-ol (6 parts), bytreating with diazomethane, according to Example 22, 2-carboxylicacidmethylester 3 n butoxy 17a methyl androsta 2,4- diene-l7fl-ol (5.87parts) was obtained.

EXAMPLE 27 Za-carboxylic acid-methylester-andr0st-4-ene-17,9- 0l-3-0neZ-carboxylic acid-methylester-3-n-butoxy-androsta-2,4- diene-17/3-ol (3parts) was dissolved in parts of 90% acetic acid and heated for 10minutes on a boiling waterbath. Then the mixture was diluted with waterand filtered. By crystallization from ethyl ether, 2-carboxylic acidmethylester -androsta 4 ene 17,8 ol 3 one (2.05 parts) was obtained,M.P. l58160 C.

EXAMPLE 28 2a-carb0xylic acid-methyl-ester-androst-4-ene-17p-0l-3-0ne-17-acetate 2-carboxylicacid-methyl-ester-3-n-butoxy-androsta-2,4- diene-17,8-ol-17-acetate (2.8parts) was treated as in EX- ample 27, to give Zea-CflfbOXYliCacid-methyl-ester-androst- 4-ene-17B-ol-3-one-17-acetate (1.92 parts).

EXAMPLE 29 Zea-carboxylic acid-methyZ-ester-l 7a-methyl-androst-4-ene-17/3-0l-3-0ne According to Example 27, Zoe-carboxylicacid-methylester-17a-methyl-androst-4-ene-17/3-ol-3-one (1.23 parts) wasobtained from 2-car-boxylieacid-methyl-ester-S-nbutoxy-l7a-methyl'androsta-2,4-diene-1713-01 (1.93parts).

EXAMPLE 30 2a-carb0xylic acid-methyl-ester-estrl-ene-I7 B-0l-3-0neFollowing the process described in Example 27, 20ccar-boxylicacid-methyl-ester-estr-4-ene-17fl-ol-3-one (1.96 parts) was obtainedfrom 2-carboxylic acid-methyl-ester- 3-n-butoxy-estra-2,4-diene-17,8-01(3.2 parts).

EXAMPLE 31 Zea-carboxylic acid-methyl-ester-ch0lest-4-en-3-0ne Followingthe process described in Example 27, 20ccarboxylic acid methyl estercholest-4-ene-3-one (2.9 parts) was obtained from 4.9 parts of2-carboxylic acidmethyl-ester-3-n-butoxy-cholesta-2,4-diene.

EXAMPLE 32 Z-carboxylic acid-chloride-3-n-but0xy-ch0lesta- 2,4-diene Asuspension of 2-carboxylic acid-3-n-butoxy-cholesta- 2,4-diene (4.84parts) in benzene (10 parts) was treated with sodium-ehtylate (0.7 part)in ethanol (10 parts). The slurry was evaporated to dryness, treatedwith benzene and again evaporated to dryness. The thus obtained solidproduct was slurried at 0 C. in a solution of 4 parts of oxalyl chloridein 20 parts of anhydrous benzene, kept 6 at the above temperature for 10minutes, then at 20 C. for 30 minutes. The slurry was filtered and thefiltrate was evaporated to dryness to give Z-carboxylicacidchloride-3-n-butoxy-cholesta-2,4-diene (4.9 parts).

EXAMPLE 3 3 Z-carboxylic acid chl0ride-3-ethoxy-androsta-2,4-

' diene-1 75-01 Following the procedure of Example 32, 2-carb0xylicacid-chloride-3-ethoxy-androsta-2,4-diene 1713 01 (2.78 parts) wasobtained from Z-carboxylic acid-3-ethoxyandr0sta-2,4-dicne-17/3-01 (2.8parts).

EXAMPLE 34 2-carb0xylic acid-chloride-S-n-but0xy-androsta-2,4- diene-J7p-ol-1 7 -acetate 2 carboxylic acid chloride-3-n-butoxy-androsta-2,4-diene-17f3-o1-17-acetate (4.65 parts) was obtained from 2 carboxylicacid-3-n-butoxy-androsta-2,4-diene-17,8-01- 17-acetate (4.6 parts),following the procedure of Example 32.

EXAMPLE 35 2-carb0xylic acid-chloride-S-n-but0xy-esfra-2,4- diene-17,8-01

2 carboxylic acid-chloride-3-11-butoxy-estra-2,4-diene- 17/3-01 (3.82parts) was obtained from 2-carboxylic acid-3-n-butoxy-estra-2,4-diene-17fl-0l (4.1 parts), following the procdureof Example 32.

EXAMPLE 3 6 Z-carboxylicacid-chl0ride-3-n-but0xy-17a-methylandr0s[a-2,4-diene-1 75-01 Followingthe process of Example 32, Z-carboxylic acid chloride 3 n butoxy 17ozmethyl androsta- 2,4-diene-17/3-ol (5.37 parts) was obtained fromZ-carboxylic acid 3 n butoxy 17a methyl androsta- 2,4-diene-l7fi-ol (6.8parts).

EXAMPLE 37 Z-carboxylic acid-amide-Sm-butoxy-ch0lesta-2,4-diene Asolution of 5.0 parts of 2-carboxylic acid chloride-3-n-butoxycholesta-2,4-diene in anhydrous benzene (50 parts) was addeddropwise during one hour to benzene parts) on a water-bath, a stream ofNH being passed through the solution during the addition and continuedfor 20 minutes thereafter. The solution was washed with water andevaporated to dryness; after crystallization, 2-carboxylicacid-amide-3-n-butoxy-cholesta 2,4 diene (4.4 parts) was obtained.

EXAMPLE 38 2-carb0xylic acid amide-3-n-butoxy-eslra-2,4-diene-17,8-01

Following the method described in Example 37, Z-carboxylic acidamide-3-n-butoxy-estra-2,4-diene-1718-01 (3.1 parts) was obtainedstarting from Z-carboxylic acidchloride-3-nbutoxy-estra-2,4-diene-175-01 (4.2 parts).

EXAMPLE 39 Z-carboxylic acid amide-3-eth0xy-andr0sta-2,4- diene-1 7/3-01chloride 3 n butoxy 17oz methyl androsta 2,4- diene-17l3-ol (3.2 parts).

EXAMPLE 41 2- (carboyl-isothiocyanate) -3-n-but0xychlesta-2,4-indene2-carboxylic acid chloride-3-nbutoxy-chloesta-2,4-diene (2.52 parts) indry \acetonitrile (75 parts) was shaken with freshly dried potassiumthiocyanate (0.53 part) for 3 hours, then filtered from potassiumchloride, and the orange filtrate distilled in vacuo, to give paleyellow 2- (carboyl isothiocyanate) 3-n-butoxy-cholesta-2,4-diene (2.12parts).

EXAMPLE 42 2-(carboyl-isothiocyanate)-3-ethoxy-androsta-2,4-diene- 17;3-01

Following the procedure of Example 41, 2-(carboyl-isothiocyanate) 3ethoxy androsta-2,4-diene-175-01 (5.3 parts) was obtained fromZ-carboxylic acid chloride-3-ethoxy-androsta-2,4diene-17 8-01 (6 parts).

EXAMPLE 43 2- (Carboy l-isothiocyanate -3-n-but0xy-andr0sta-2,4-diene-17,8-0l-17-acetate Following the method of Example 41,2-(carboyl-isothiocyanate) 3 n butoxy-androsta-Z,4-diene-17fi-ol-17-acetate (2.76 parts) was obtained from 2-carboxylic acid chloride 3 nbutoxy-androsta 2,4 diene-17,8-ol-17- acetate (3.1 parts).

EXAMPLE 44 2-(carboyl-isothiocyamite)-3-n-but0xy-estra-2,4-diene- 17fl-ol Following the method of Example 41, 4.73 parts of 2 (carboylisothiocyanate)-3-n-butoxy-estna-2,4-diene- 17B-ol were obtained fromZ-(carboxylic acid chloride) 3-n-butoxy-estra-2,4-diene-17fi-ol (5.1parts).

EXAMPLE 45 2- (cal-boy l-z'sothiocyanate -3-n-but0xy-1 7oc-mcthylandrosta-2,4-diene-1 7fi-ol Following the method described in Example41, 2-(carboyl isothiocyanate) 3 n-butoxy-17a-methyl-androsta-2,4-diene-17B-ol (3.12 parts) was obtained from 2-carboxylic acidchloride-3-n butoxy-17a-methyl-androsta-2, 4-diene-17B-ol (3.75 parts).

EXAMIPLE 46 2- Carboy l-isocyanate) -3-n-but0xy -ch0lesla-2,4-diene2carboxylic acid chloride-3-n-butoxy-cholesta2,4-diene- (2.50 parts) indry acetonitrile (75 parts) was shaken with freshly dried potassiumcyanate (0.48 part) for 3 hours, then filtered from potassium chlorideand the filtrate was distilled in vacuo, to giveZ-(carboyl-isocyanate)-3-n-butoxy-cholesta-2,4-diene (2.2 parts).

EXAMPLE 47 2- (carboyl-isocyanate) -3-n-but0xy-1 7a-metlly l-androsta-2,4-diene-1 7B-0l 8 EXAMPLE 48 N -2-( 3 -n-but0xy-ch0lesta-2,4 -diene)-carb0y l-thiourea 2 (carboyl isothiocyanate) 3 n butoxycholesta-2,4-diene (0.525 part) in anhydrous ether (50 parts) wastreated with 3.4 N methanolic ammonia (3 parts) and N-2- 3-n-butoxy-cholesta-2,4-diene -carboyl-thiourea (0.475 part) wasobtained.

EXAMPLE 49 N -2- (3-n-but0xy ch0lesta-2A -di ene) -carb0y l-N -butylthiourea 2 (carboyl isothiocyanate) 3 n butoxy cholesta-2,4-diene (0.70part) in anhydrous ether (60) parts were treated with n-butylamine (0.15part) in ether; N-2- (3 n butoxy cholesta 2,4diene)-carboyl-N-butylthiourea (0.52 part) was obtained.

EXAMPLE 50 2 (carboyl isothiocyanate) 3 n butoxy cholesta- 2,4-diene(1.05 parts) in ethyl ether (60 parts) was treated with 2, 3', 5'-tri-O-benzoyl-fl-D-ribofuranosylamine (0.94 part) in ethyl ether (15parts). After quite a vigorous reaction 1.12 parts ofN-2-(3-n-butoxy-cholesta 2,4 diene) carboyl N (2,3,5', tri Obenzoyl-fl-D-ribofuranosyl)thiourea were obtained.

EXAMPLE 5 1 N -2-(3-n-but0xy-estra-2,4-diene-1 7fl-0l) -carb0yl-N-ethyl-thiourea 2 (carboyl isothiocyanate) 3 n butoxy estra-2,4-diene-l7fl-ol (0.52 part) in anhydrous ethyl ether (25 parts) wastreated with 3.5 N ethylamine in ethanol (3 parts) N-2- (3-n-butoxy-estra-2,4-diene--01)-carboyl- N'-ethyl-thiourea (0.38 part)was obtained.

EXAMPLE 5 2 To a solution of 2(carboyl-isothiocyanate)-3-n-butoxy-17a-1nethyl-androsta-2,4-diene-175-01 ('2 parts) in ether (30 parts) wasadded 0.5 part of 33% methanolic methylamine. The solution wasevaporated to dryness and by crystallization from methanol-ether,N-2-(3-n-butoxy- 17a methyl androsta 2,4 diene 17B ol) carboyl-N'-methyl-thiourea (1.26 parts) was obtained.

EXAMPLE 5 3 2 (carboyl isothiocyanate) 3 ethoxy androsta-2,4-diene-17fl-ol (0.63 part) was treated with ether (50 parts)containing 3,5-di-O-benzoy-l-2-deoxy- 3-D-ribofuranosyl-amine (0.58part) dissolved therein; after a night at room temperature, 0.59 part ofN-2-(3-ethoxy-androsta- 2,4 diene 17,8 o1) carboyl 3,5 di O benzoyl-2'-deoxy-fl-D-ribofuranosylthiourea were obtained.

EXAMPLE 54 N 2-(3-n-butoxy-androsta-2,4-diene-17fl-0l-17-acetate)-carboyl N'-(2,3,5'-tri-O-benz0yl-p-D-ribofuranosyl) thiourea 2 (carboylisothiocyanate)-3-n-butoxy-androsta-2,4- diene-17fl-ol-l7-acetate (0.92part) in ethyl ether (50 parts) was treated with2',3',5-tri-O-benzoyl-{3-D-ribofuranosyl-amine (0.98 part) in ether (17parts); after vigorous stirring, N-2-(3-n-butoxy-androsta-2,4-diene- 175ol 17-acet'ate)-carboyl-N'-(2',3',5-tri-O-benzoyl-fiD-ribofuranosyD-thiourea (0.86 part) was obtained.

9 EXAMPLE 55 EXAMPLE 6 N 2- (3-n-butoxy-cholesta-ZA-diene) -carb0yl-N'-(2,3',5'- tri-O-benzoyl-fi-D-ribofuranosyl) -urea To a solution of2-(carboyl-isocyanate)-3-n-butoxycholesta-2,4diene (0.5 part) in ethylether (50 parts) was added 2,3,S-tri-O-benzoyl-fi-D-ribofuranosyl-amine(0.45 part) in ether (30 parts). After 24 hours, N-2-(3-n-butoxycholesta2,4-diene)-carboyl-N'-(2,3,5'-tri-O-benzoyl-B-D-ribofuranosyl)-urea(0.62 part) was obtained.

EXAMPLE 57 2 (carb oyl-isocyanate)-3-n-butoxy-androsta-2,4-diene-1718-01 (0.59 part) was treated with 3,5-di-O-benzoyl-2-deoxy-fi-D-ribofuranosyl-amine (0.60 part) in ether (52 parts). After anight, N-2-(3-n-butoxy-androsta-2,4-diene 17B-ol)-carboyl-N'-(3',5'-di-O-benzoyl-fi-D-2'-de' oxy-ribofuranosyl)-urea(0.73 part) was obtained.

EXAMPLE 58 N 2-(3-n-butoxy-17a-melhyl-androsta-2,4-diene-1 75-01).carb0yl-N'-methyl-urea To a solution ofZ-(carboyl-isocyanate)-3-n-butoxy- 17a-methyl-androsta-2,4-diene-175-01(0.56 part) in ether (20 parts), 2 parts of 33% methanolic-methylaminewere added. After 6 hours, the thus obtained solution was evaporated todryness and crystallized from methanol, obtaining therebyN-2-(3-butoxy-l7a-methyl-androsta-2,4-diene-17/8-ol) -carboyl N methylurea (0.48 part).

EXAMPLE 59 N 2- (3-n-b ut0xy-andr0sta-2,4-diene-1 7B-ol-l 7-acetatecarboyl-N'-n-pentyl-urea A solution of2-(carboyl-isocyanate)-3-n-butoxy-androsta-2,4-diene-17,8-01-17-acetate(0.47 part) in benzene (30 parts) was refluxed with pentylamine (2parts) in benzene parts). The mixture was evaporated to dryness and bycrystallization from methanol, 0.51 part ofN-2-(3-n-bu-toxy-androsta-2,4-diene-176-01 17 acetate)-carboyl-N'-n-pentyl-urea was obtained.

EXAMPLE 60 N -2- (androst-4 -ene-3-0ne-1 7,8-0l-1 7-acetate) -carb0yl- N'-pentyl-urea A solution of N-2-(3-n-butoxy-androsta-2,4-diene-17B-ol-17-acetate)-carboyl-N'-pentyl-urea (0 .3 part) in 85% acetic acid (4parts) was heated on a water bath for 15 minutes. The solution wasdiluted with water and, after filtering and crystallizing from methanol,N-2-(androst- 4-ene-3-one-l7fi-ol-17-acetate)-carboyl-N' pentyl urea(0.18 part) Was obtained.

Za-cyano- Sa-andmstane-17fl-ol-3-one (40 parts) in benzene (1500 parts)was refluxed with ethylene glycol (46 parts) for 16 hours, along withp-t-oluenesulphonic acid (1.2 par-ts), the water being continuouslyremoved. Pyridine (6 parts) was added, then the mixture was Washed withwater and evaporated to dryness. After crystallization from acetone,3,3-ethylenedioxy-2a-cyano-5a-androstane-17/3-ol- (33.8 parts) wasobtained, M.P. 232- 234 C.

EXAMPLE 62 3,3-ethylenedi0xyJot-cyan0-5u-andr0stane-17-0112 3,3ethylenedioxy-2a-cyano-5a-androstane-175-01 (20 parts) was dissolved indimethylformamide (380 parts) and acetone (20 parts), cooled to 2 C.,and 40 parts of Jones reagent were added thereto in 5 minutes, withstirring; then the mixture was kept at 5 C. for 5 minutes. It wasdiluted with water and filtered; by crystallization from acetone3,3-ethylenedi0xy-2a-cyanO-Sa-andmstane- 17-one (14 parts) was obtained,M.P. 239-242 C.

EXAMPLE 63 2a-acetyl-3,3-ethylenedioxy-5m-androstane-17(3-01 To asolution of 3,3-ethylenedioxy-2u-cyano-5a-androstane-IZB-ol (5 parts) inanhydrous anisole parts) was added a 32.68% ethereal solution ofmethyl-magnesium bromide (80 parts). When the ether Was evaporated, thesolution was kept for 20 hours at C. The mixture was treated with NH Cl,steam-distilled and extracted with methylene chloride; the solution wasevaporated to dryness. By crystallization from methanol,20cacetyl-3,3-ethylenedioxy-5a-androstane-17/3-01 (3.5 parts) wasobtained, M.P. 221-223 C., (a) =6 (chloroform).

EXAMPLE 64 Za-aCety l-3,3-ethylenedi0xy-1 7 a-methy [-5 C!- androstane-I7/3-0l Following the procedure of Example 63, except that2a-cyano-3,3-ethylenedioxy-5a-androstane 17 one (3 parts) was used,2u-acetyl-3,3-ethylenedioxy-17a-methyl- ;Sa-androst-ane-UB-ol (2.2parts) was obtained; M.P. 177- 178.5 C.; (a) =-'18 (chloroform).

EXAMPLE 65 2ot-carb0xylfc acid-methylester-Sa-androstane-l 7B- 0l-3-0neTo a solution of 3,3EthYI6I16diOXY-2-a-CY3110-Swandl'O- stane- 17/3-ol(25 parts) in ethylene glycol (300 parts) were added 75 parts ofpotassium hydroxide in 75 parts of water, and the mixture was refluxedfor 40 hours; then it was diluted with Water, filtered and the filtratewas acidified. The crude acid was precipitated, and, after filtering andcrystallizing from ethyl ether, Za-carboxylicacid-3,3-ethylenedioxy-5a-androstane-l75-01 (20 parts) was obtained,M.P. 229-233 C. The above compound was suspended in 400 parts of benzeneand a 2% of diazomethane ethereal solution parts) was added. After anight at room temperature, the solvent was evaporated and the residuecrystallized from MeOH, 3,3-ethyl enedioxy-2,2-carboxylic acidmethylester-5a-androstane- 17,8-ol (20.2 parts) being obtained, M.P.179l80 C. The above compound was de-ketalized by heating its solution in90% acetic acid (300 parts) on a water bath for 2 hours. After dilutionwith water, filtration and crystallization from methanol, 2-carboxylicacid-methylester-5aandrostane-17B-ol-3-one (13 parts) Was obtained, M.P.184l86 C.; (a) =+69 (chloroform).

EXAMPLE 66 2u-carboxylic acid-3,3-ethylenedioxy-5a-andr0stane- 17/3-01-1 7 -acetate 2oz carboxylicacid-3,3-ethylenedioxy-Sa'androstanel7fi-ol (1.6 parts) was dissolved inpyridine (8 parts) and acetic anhydride (4 parts), and allowed to standfor 24 hours 2a-carboxylic acid 3,3ethyIenediOXy-Sa-androstane-17/3-ol-17-acetate (1.62 parts) was obtainedthrough dilution with Water and crystallization from ethyl ether.

1 1 EXAMPLE 67 3,3-ethylenedixy-2oc-cyano-cholestane Following theprocess described in Example 55, except that 2-cyano-cholestane-3-one(25 parts) was used, 3,3- ethylenedioxy-2a-cyano-cholestane (22 parts)was obtained, M.P. 163-166 C.

EXAMPLE 68 2-carboxylic acid-methyl-ester-3-methoxy-5uandrost-Z-ene-l7/3-0l To a solution of 2-carboxylicaCid-methyI-ester-Sa-androstane-3-one-17fl-ol (2 parts) in 20 parts ofethyl ether, containing a BF -etherate solution (4 parts), was added adiazomethane ethereal solution (10 parts). After 6 hours at roomtemperature, and after washing with water and with an aqueous dilutesodium-bicarbonate solution, the mixture was evaporated to dryness, toobtain 2-carboxylic acid-methylester 3 methoxy-5a-androst-2-ene- 1713-01(1.75 parts).

EXAMPLE 69 Z-carboxylic acid-methylester-S-methoxycholest-Z-ene2-carboxymethyl-ester-cholestane-3-one (R. A. Nelson and R. N. Schutz,J.A.C.S. 80, 6630, 1958) (5 parts), treated according to the aboveexample, gave 2-carboxy1ic acid-methylester-3-methoxy-cholest-2-ene(4.12 parts).

EXAMPLE 70 2-carboxylicacid-methylester-3-eth0xy-17amethyl-androst-Z-ene-I 713-01 Following theprocess described in Example 68, except that 2-carboxylicacid-methyl-ester-17a-methy1-5a-androstane-3-one (5 parts) anddiazoethane were used, 2-carboxylicacid-methylester-3-ethoxy-17ot-methyl-5a-androst- 2-ene-l7fl-ol (4.8parts) was obtained.

EXAMPLE 71 2-carb0xylic acid-methylester-3-n-butoxy-Saandrost-Z-ene-I7,8-0l

2-carboxylic acid methyl-ester-Sa-androstan-l75-01-3- one (1.2 parts) intoluene (30 parts) was refluxed for 6 hours with n-butanol (1.7 parts)and p-toluenesulphonic acid (0.027 part), the water being removed. Themixture was neutralized with pyridine (1 part) and after severalwashings with water and alkali, it was evaporated to dryness, therebyobtaining 2-carboxylicacid-methylester-3-n-butoxy-5ot-androst-2-ene-17/3-01 (0.97 part).

EXAMPLE 72 To 2-carboxylic acid-ethylester-3-ethoxy-17a-methyl-5a-androst-2-ene-17fi-ol (8 parts) in anhydrous ethanol (10 parts) wasadded sodium ethoxide (1.45 parts) and the mixture was kept at roomtemperature for 2 hours. The mixture was evaporated to dryness andtreated several times with anhydrous benzene, the suspension of thesodium salt of 3-ethoxy-17u-methy1-5a-androst-Z-ene-17/3-ol-2-carboxylic acid being evaporated to dryness each time. The salt wasthen slurried in anhydrous benzene (30 parts), then oxalyl chloride (6.2parts) was added thereto at 0 C. After 20 minutes at room temperature,the slurry was filtered and the filtrate was evaporated to dryness togive 2-carboxylicacid-chloride-3-ethoxy-17amethyl-5a-androst-2-ene-17fi-ol (7.2 parts).This latter compound was suspended in anhydrous acetonitrile (40 parts),anhydrous potassium isothiocyanate (2.2 parts) was added, and the slurrywas stirred at room temperature for 3 hours. After filtering to removesalts, the solution was evaporated and 2-carboyl-isothiocyanate-3-eth-12 oxy-17a-methyl-5u-androst-2-ene-173-01 (7.1 parts) was obtained.

EXAMPLE 73 2-carb0yl-iso-cyanate-3-etlzoxy-1 7a-methyl-Saandrost-Z-ene-l 7fl-0l Following the process of the above example,except that 2-carboxylicacid-chloride-3-ethoxy-17u-methyl-5aandrost-2-ene-l7f3-ol (3.5 parts)and potassium cyanate were used,2-carboyl-isocyanate-3-ethoxy-17a-methyl-5aandrost-2-ene-l7fl-ol (2.6parts) was obtained.

EXAMPLE 74 N -2 a- 3 ,3 -ethylened i0xy-5 ot-androstane-l 7fi-0l-1 7acetate -carb0yl-urea and N -butyl-urea To a solution of sodiummethoxide (1.08 parts) in methanol, 3,3-ethylenedioxy 5aandrostane-17fi-ol-l7- acetate-2a-carboxylic acid (8.4 parts) Was added;after 5 minutes the solution was completed; it was evaporated to drynessand repeatedly treated with benzene, then evaporated to dryness undervacuum. The residue was slurried in benzene and oxalyl chloride (6parts) was added at 0 C.; then the precipitate was filtered and thefiltrate evaporated to dryness. 2a-carboxylic acid chloride (7.2 parts)was obtained, which was slurried in anhydrous acetonitrile (50 parts)and anhydrous potassiumcyanate (1.7 parts) was added. The separatedpotassium chloride was filtered and the filtrate was concentrated todryness to obtain2a-carboyl-isocyanate-3,3-ethylenedioxy-5a-androstane-17B-ol-17-acetate(7.05 parts). To this compound (3 parts) in anhydrous ethyl ether (15parts), 5 parts of a saturated rnethanolic ammonia solution were added,thereby obtainingN-2a-(3,3-ethylenedioxy-5a-androstane-175-01-17-acetate)-carboyl urea(2.8 parts). In a similar manner, N-2a-(3,3-ethylenedioxy-5ot-androstane-17fl-o1-17-acetate)-carboyl N butylurea (2.6 parts) wasobtained, starting from an etheral solution of2a-carb0yl-isocyanate-3,3-ethylenedioxy-5a-androst-ane-17fl-ol-17-acetate(3 parts) with n-butyl-arnine (2 parts).

EXAMPLE 75 N -2 (5 a-androstane-j -0I1e-1 7B-0l-1 7 -acetatecarboyl-urea N -2 (3,3ethylenedioxy-5a-androstene-17fi-ol-17-acetate)-carboyl-urea (1.2 parts)was heated with acetic acid (4 parts).N-2-(5a-andr0stane-3-one-17B-ol-17-acetate)-carboyl-urea (0.72 part) wasobtained after heating 10 minutes on a water bath, dilution with waterand crystallization from methanol.

EXAMPLE 76 N -2-(5 a-androstane-3-one-1 75-0l-1 7-acetatecarboyl-N-'-buty l-w'ea Following the process of Example 75, except thatN 2a(3,3-ethylenedioxy-5a-androstane-17fl-ol-17-acetate)-carboyl-N'-butyl-urea(2.2 parts) was used as starting material, N-2-(5a-androstane-3one-17,8-ol-17-acetatc)-carboyl-N'-buty1-urea (1.63 parts) was obtained.

EXAMPLE 77 N -2- (5 u-androst-Z-ene-3-but0xy-1 7B-0l-1 7 -acetate)carboyl-urea N 2-(5a-androstane-3-one-17B-o1-17-aoetate)-carboylurea(1.8 parts) in toluene (30 parts) along with butanol (3 parts) andp-toluene sulphonic acid (0.08 part) was bolied to remove water. Afterneutralization with pyridine, the mixture was washed with water,evaporated to dryness and the residue crystallized from methanol toobtain 1.12 parts of N-2-(5a-androst-2-ene-3-n-butoxy-17p-ol-l'l-acetate)-carboyl-urea.

1 3 EXAMPLE 7s N-Z- (3-11-buIOxy-Sa-androst-Z-ene-Z 7 [101-1 7 -acetateCarboy l-N-butyl-urea Following the process described in Example 77,except that N 2-(5u-androstane-3-one-17,B-ol-l7-acetate)-carboyl-N-butyl-urea (4.1parts) was used, N-2-(3n-butoxy- 5a-androst 2ene-l7fi-ol-l7-acetate)-carboyl-N'-butylurea (3.1 parts) was obtained.

EXAMPLE 79 To a slurry of2-carboyl-isothiocyanate-3-ethoxy-5ocandrost-2-ene-l7fi-ol (2.1 parts)in anhydrous ethyl ether (40 parts) was added2,3,5-tri-O-benzoy1-;3-D-ribofuranosylamine (2.5 parts). After 12 hoursat room ternperature, N 2 -(3- ethoxy-17oc-methyl-5a-andrOst-Z-ene-1713-01)-carboyl-N'-(2,3',5-tri-O-benzoyl-fi D ribofuranosyl)-thiourea(2.4 parts) was obtained.

EXAMPLE 80 The process described in Example 79 was followed, except that2-carboyl-isocyanate-3-ethoxy-l7a-methyl-5aandrost-2-ene-17B-ol (1.8parts) was used. N-2-(3- ethoxy17a-methyl-5u-andrOst-Z-ene-l7/3-ol)-carboyl-N- (2,3,5'tri-O-benzoyl-fi-D-ribofuranosyl)-urea (1.76 parts) was obtained.

EXAMPLE 81 N -2- (3 -ethxy-] 7 a-methyl-S oc-tllZdI'OSf-Z -ene-1 753-01)Carboy l-N-n-hexyl-thiourea To a slurry of2-carboyl-isothiocyanate-3-ethoxy-5uandrost-2-ene-l7fi-ol (0.4 part) inbenzene (30 parts), there was added n-hexyl-amine (0.3 part) in benzene(5 parts). The slury was kept at room temperature for 30 minutes, thenat 60 C. for one hour. Then it was evaporated to dryness andcrystallized from methanol to obtainN-Z-(3-6thOXY-l7ocmethyI-Sa-andrOst-Z-ene 17,8-ol)-carboyl-N-n-hexy1-thiourea (0.43 part).

EXAMPLE 82 N -2- 3-eflz oxy-J 7 a-methyl-S a-androst-Z-eneJ 716-01) carb0 y l urea To a slurry of 2carboyl-isocyanate-3-ethoxy-17amethyl-5oc-androst-2ene-1713-01 (0.5part) in 10 parts of ether, was added 3.8 N methanolic ammonia (2.5parts). The solid was completely dissolved; thereafter N-2-(3-ethoxy-17a-methly-Sa-andrOst-Z-ene-17fl-ol) -carboyl-urea (0.39 part)was obtained as a precipitate.

We claim:

1. A compound of the formula where R is a member selected from the groupconsisting of H and CH R is a member selected from the group consistingof OH, 0R R being an acyl radical derived from an aliphatic acid of from2 to 10 carbon atoms, and 2-methy1-isoheptyl; R is a member selectedfrom the group consisting of H and lower alkyl; R is alkyl of from 1 to4 carbon atoms; R is a member selected from T4 the group consisting ofOH, OMe, OEt, CH

Cl, NH CNS, CNO,

R; .g o

where R is a member selected from the group consisting of H and CH R isa member selected from the group consisting of OH, 0R R being an acylradical derived from an aliphatic acid of from 2 to 10 carbon atoms, andZ-methyl-isoheptyl; R is a member selected from the group consisting ofH and lower alkyl; and R is a member selected from the group consistingof CN,

R being a member selected from the group consisting of H, alkyl of from1 to 6 carbon atoms, ribosyl, 2-deoxyribosyl,2',3,5'-tri-O-benzoyl-ribosyl and 3,5'-di-O-benzoy1-2'-deoxyribosyl.

3. A compound of the formula where R is a member selected from the groupconsisting of H and CH R is a member selected from the group consistingof OH, 0R R being an acyl radical derived from an aliphatic acid of from2 to 10 carbon atoms, and 2-methylisoheptyl; R is a member selected fromthe group consisting of H and lower alkyl; R is a member selected fromthe group consisting of Cl, CNS,

S NH- 1NHR and NHii-NHR R being a member selected from the groupconsisting of H, alkyl of from 1 to 6 carbon atoms, ribosyl,2'-deoxyribosyl, 2',3,5- tri-O-benzoyl-ribosyl and3,5'-di-O-benzoyl-2'-deoxyribosyl; and X is a member selected from thegroup consisting of a single and a double bond.

References Cited by the Examiner UNITED STATES PATENTS 3,062,843 11/1962Knox 260397.1 3,146,231 8/1964 Dean 260-23955 3,153,647 10/1964 Shapiroet al 260239.55

ELBERT L. ROBERTS, Primary Examiner. J. R. BROWN, Assistant Examiner.

1. A COMPOUND OF THE FORMULA